Non-steroidal anti-inflammatory drugs (NSAIDs) have demonstrated high therapeutic value, especially for the treatment of inflammatory conditions or diseases, like osteoarthritis and rheumatoid arthritis.
A great variety of NSAIDs dosage forms is available on the market.
Usually, the NSAIDs have to be taken several times a day, which can generate an important compliance issue, particularly with patients population like the elderly.
As understood in the prior art, enteric or delay release coatings are not an efficient method for the delivery of NSAIDs due to the inability of such formulations to provide or achieve a sustained therapeutic effect due to the lack of prolonged release of the pharmaceutical agent. Also the concurrent administration of enteric coated or delayed release NSAIDs with food or the presence of food in the stomach may lead to dose dumping and unwanted secondary effects.
Optimizing the release of one or several drugs from a dosage form is an important way of guiding their pharmacological action and of great benefit for patient treatment. Extended release (identified by the abbreviations ER or XR) is the most current and official terminology to define a controlled availability of the drug alongside the gastrointestinal tract. Other expressions used in the scientific literature to define the same profile are: sustained, controlled, prolonged, retard or similar.
Modified releases have been debated between Experts in the Pharmaceutical Technology and are frequently defined in scientific and official documents.
In the NSAIDS therapeutic class, the United States Pharmacopeia, 25 edition, pages 554-555, describes the Diclofenac Sodium Delayed-Release Tablets in an Official Monograph.
Interestingly, a proposal of a Diclofenac Sodium Extended-Release Tablets monograph has been recently published on the USP Pharmacopeial Forum (Vol. 2003 pp. 319-320).
More details on Diclofenac Sodium, i.e., about Pharmacokinetics data, can be found in the Prescribing Information document made by Novartis, the Company which commercialised the drug initially.
The NSAIDS exert most of their anti-inflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth trough inhibition of prostaglandin G/H synthase, also known as cyclooxygenase (COX). Inhibition of COX-1 causes a number of side effects including inhibition of platelet aggregation associated with disorders of coagulation, and gastrointestinal side effects. The gastrointestinal side effects are due to a decrease in the biosynthesis of prostaglandins which are cytoprotective of the gastric mucosa. The prevalence of gastrointestinal side effects is similar among “acute” and “chronic” NSAID users and affects especially the elderly.
A high incidence of side effects has historically been associated with the use of classic cyclooxygenase inhibitors, all of which are about equipotent for COX-1 or COX-2, or which are COX-1.
In view of the still very large therapeutic use of classic NSAIDs, several approaches have been undertaken to minimise the drugs' adverse effects.
For many years, neutralization of gastric acid with antiacids was the only relief from the gastrointestinal pain induced by ulcers. More recently agents called “proton pomp inhibitors” have been recommended and used. They provide a more specific class of inhibitors of gastric secretion in mammals, including humans, by blocking the final step of acid production.
The documents U.S. Pat. No. 6,365,184, U.S. Pat. No. 6,544,556 and U.S. Pat. No. 6,613,354 describe an oral pharmaceutical dosage form comprising a “proton pomp inhibitor” and one or more NSAID(s) in a fixed formulation, and their use in the treatment of gastrointestinal side-effects associated with NSAID treatment.
The use of prostaglandins is an improved way to minimize the gastrointestinal ulcerations induced by the oral administration of NSAIDs, such PGE1, PGE2, misoprostol and derivatives thereof.
Co-administering exogenous prostaglandins, particularly misoprostol, in association with NSAIDS is a “natural” way of preventing NSAID-associated ulcers and ulcer complications as described in Silverstein F. E., Digestive Diseases and Sciences 1998; 43: 447-458.
Moreover, dosage forms based on misoprostol or anti-ulcerogenic prostaglandins are cheaper than the commercially available “proton pump inhibitors”. This results in “fixed dose combination products” priced lower, which is an important parameter in the today Social Security resources.
More details on Misoprostol, i.e., about Pharmacokinetics document data, can be found in the Prescribing Information document made by Searle, the Company which commercialised the drug initially.
Interestingly, the European Pharmacopeia Commission has, in June 2003, proposed a monograph for the Misoprostol active ingredient. The document is Monograph No.: 1731 with additional reference PA/PH/Exp.10B/T (02)140 ANP and is currently submitted for comment to the relevant authorities.
However, prostaglandins are unstable compounds and have been shown degrading readily in the presence of NSAIDs.
The documents U.S. Pat. No. 5,601,843, U.S. Pat. No. 6,193,779, U.S. Pat. No. 6,537,582 and WO99/65496 describe different ways of combining sodium diclofenac Enteric- or Delayed-Coated Releases with a prostaglandin. However, these approaches have the drawbacks of the enteric or delay releases dosage forms highlighted here above.
Therefore, there is a need in the art to provide a composition for administering an NSAID sustained release dosage form wherein the undesirable gastrointestinal side effects of the drug are minimised.